Combined Infusion Research Articles

Feasibility and Toxicity of a Modified Dose Intensive R- CODOX-M/IVAC for HIV-Associated Burkitt and Atypical Burkitt Lymphoma(BL): Preliminary Results of a Prospective Multicenter Phase II Trial of the AIDS Malignancy Consortium (AMC).

Abstract 3673Poster Board III-609 BackgroundThe treatment of HIV associated BL remains controversial with some concerned about the potential toxicity of the dose-intensive regimens typically used as treatment for BL in HIV seronegative patients. However, less intensive regimens have a high relapse rate. We modified the CODOX-M/IVAC regimen with the goal of preserving efficacy while improving tolerability, particularly treatment related mortality (TRM). The primary object was to improve the 1 year overall survival (OS) from 65% based on historical reports to 85%. An interim analysis was planned to exclude excessive TRM. MethodsMajor modifications of the original US NCI regimen include the addition of rituximab, reduction in cyclophosphamide to 800 mg/m2 × 2 days, vincristine 2 mg cap, methotrexate 3000 mg/m2, reduction of lumbar punctures using combination chemotherapy and infusion of the IVAC portion for the high risk patients. Antibiotic prophylaxis and growth factor support were specified as grade IV hematopoietic toxicities were reported in 100% of patients in the original regimen. HAART therapy was continued at the discretion of the local investigator. ResultsAs of June 2009, 22 of 31 planned patients have accrued and the study is ongoing. Baseline characteristics include: Classical Burkitt's, 95%; Low/High Risk, 9/91%; Median (range) Age 40 (19 – 55); CD4 count 290 (0 – 1260), CD4 <100, 5 ( 27%); HIV viral load 15,600 (48 – 715,881).Treatment StatusN (%)Treatment Completed per protocol13 (65%)Early termination due to adverse event*3 (14%)Early termination due to disease progression (central nervous system)1 (5%)Early termination due to patient withdrawal2 (9%)Early termination – counts did not recover within time frame to begin cycle 41 (5%)Treatment termination-reason not given1 (5%)Treatment ongoing2 (9%)*Terminations due to adverse events: 1 pt. due to grade 4 thrombocytopenia and grade 3 infection possibly related to doxorubicin and cyclophosphamide; 1 pt. due to grade 3 left hemiparesis possibly related to cytarabine and vincristine; 1 pt. due to grade 3 confusion unrelated to treatment.# of pts with Grade 3/4Treatment related toxicity: 15 with any, 13 hematologic, 7 with infection including 5 febrile neutropenia, 6 metabolic including 1 tumor lysis syndrome, 4 neurologic, 2 thrombotic and 1 each coagulation, GI or pain. Notably, only 2 patients had grade 1/2 stomatitis/mucositis and none had grade 3/4.Two patients died after treatment. Patient #1 died 3 months after completing treatment due to a fungal infection. Patient #4 died 5 months after completing treatment due to primary malignancy.<>Overall Survival<>N22<>Median (months)17.0<>One-year overall survival (95% CI)85.7% (60%, 100%) ConclusionsThe early stopping rule was not invoked for this dose modified, but intensive trial of HIV associated Burkitt's. In fact we had had no TRM. Notably, despite concerns raised in AMC 010, our prior study of DLBCL, rituximab did not appear to increase toxicity. Only 4 patients withdrew due to adverse events and 1 did not complete the protocol. The latter patient remains in remission, but has less than 1 year of follow up. Grade 3/4 toxicities were markedly reduced. These results compare favorably with 2 studies that excluded HIV + pts. Magrath (1995) originally reported 100% grade 4 hematologic and 20% mucositis in 39 adults, 33 children (92% 2 yr EFS). MRC/NCRI LY10 trial (Mead 2008) also reduced methotrexate(3gr/m2), but reported 9% treatment related deaths (64% 2 yr OS). Treatment efficacy thus far appears preserved in AMC 048 with our modifications which reduced TRM and morbidity. Correlative studies to improve our understanding of HIV-BL are pending. Accrual is ongoing. With ongoing enrollment and follow-up, it is possible the primary objective of 1 year OS of 85% may be achieved. Disclosures:No relevant conflicts of interest to declare.

Abstract 5148: Coexistence of Functional Angiotensin II Type 2 Receptors Mediating Both Vasoconstriction and Vasodilation in the Human Forearm Circulation

Angiotensin (Ang) II type 2 (AT 2 ) receptors have been shown to mediate vasodilation in animal models, but data to support this concept in humans have failed to clearly define AT 2 receptor-dependent effects. In this study, therefore, we investigated the hemodynamic response to modulation of AT 2 receptors under different conditions in healthy humans (n=7) by use of the forearm perfusion technique. Intra-arterial infusion of graded doses of Ang II (12.5, 25 and 50 pmol/min) led to concentration-dependent vasoconstriction (−51±4% [mean±SEM] was the maximum decrease in forearm blood flow (FBF) from baseline; P&lt;0.001). The Ang II type 1 receptor antagonist telmisartan (30 μ g/min) induced a mild increase in unstimulated FBF (15±5%; P=0.10) and reversed the vasoconstrictor effect of Ang II into vasodilation (15±4%; P=0.02). The AT 2 receptor antagonist PD 123,319 (10 μ g/min) also resulted in a mild vasodilation (16±3%; P=0.08) and blunted the vasoconstrictor effect of Ang II (−8±3%; P=0.57). Most importantly, combined infusion of telmisartan and PD 123,319 was associated with a greater vasodilator effect (28±5%; P=0.02) than separate blockade of each Ang II receptor subtype; this response was unrelated to endothelial, nitric oxide (NO)-dependent mechanisms, because it was unaffected (27±5%; P=0.03) by the “NO clamp” (NO synthase inhibitor L-NMMA (4 μ mol/min) coinfused with the NO donor sodium nitroprusside (0.2 to 0.4 μ g/min) in order to simulate normal basal NO activity during complete inhibition of NO synthesis). By contrast, AT 2 receptor challenging with the ligand CGP 42112A (2 and 4 μ g/min) resulted in a vasodilator response (37±5% at the highest dose; P=0.02) that was abolished by the NO clamp (3±1%; P=0.94). In conclusion, AT 2 receptors contributing to Ang II-mediated vasoconstriction, likely located on vascular smooth muscle, coexist in the human forearm circulation with functional endothelial AT 2 receptors, mediating NO-dependent vasodilation. These results suggest that imbalance between these opposing effects in conditions with endothelial dysfunction contribute to Ang II-mediated vascular damage. Our current findings might also have implications for strategies targeting Ang II for treatment of hypertension.

P13 Prevalence of rheumatic disorders in a rural population of South India, Kerala using the WHO-ILAR COPCORD Bhigwan model

Rheumatoid arthritis (RA) has been associated with significant morbidity and economic burden. Traditional pharmacotherapy (eg, NSAIDs, corticosteroids, disease-modifying antirheumatic drugs [DMARDs]) can be inadequate in controlling symptoms and disease progression. Abatacept is the first selective co-stimulation modulator approved by the US Food and Drug Administration for the management of RA. It is a fusion protein developed to modulate the T -cell co-stimulatory signal that is mediated through the CD28-CD80/86 pathway.The objective of this manuscript was to review the clinical pharmacology, pharmacokinetic and pharmacodynamic properties, tolerability, and clinical efficacy of abatacept.MEDLINE and International Pharmaceutical Abstracts were searched through June and May, respectively, of 2006 using the term abatacept or CTLA4-Ig. All prospective, randomized, Phase II and III trials, and their extension phases, were included.Phase II and III clinical trials found that abatacept, at a dose of 10 mg/kg administered as a short IV infusion in combination with DMARDs, was associated with significant clinical benefit in patients with active RA. After 6 months of treatment, the American College of Rheumatology (ACR) criteria for 20% clinical improvement (ACR20 response) was attained in 41.9% to 67.9% of patients who received abatacept compared with 19.5% to 39.7% of patients who received placebo (P < 0.001). The percentages of patients achieving the ACR criteria for 50% and 70% clinical improvement (ACR50 and ACR70) were 20.3% to 39.9% and 10.2% to 19.8%, respectively, in the groups that received abatacept compared with 3.8% to 16.8% and 1.5% to 6.5%, respectively, in the patients who received placebo (P = 0.03 and P < 0.001). Additionally, abatacept was found to improve disease activity, physical function, pain, and health-related quality of life (HRQOL). The most commonly reported adverse effects associated with abatacept treatment were headache (18.2%), upper respiratory tract infection (12.7%), nasopharyngitis (11.5%), and nausea (11.5%). The incidences of infections and serious infections were higher in the group that received abatacept compared with patients who received placebo (53.8% vs 48.3% and 3.0% vs 1.9%, respectively; P not reported). No significant between-group differences in mortality were found.Available evidence suggests that abatacept was effective in controlling symptoms and improving HRQOL in patients with active RA and an inadequate response to DMARD therapy. The most commonly reported adverse effects associated with abatacept treatment were headache, upper respiratory infection, nausea, and nasopharyngitis. Additional trials are needed to determine the long-term safety profile of this agent and whether the clinical benefits of abatacept found in the current clinical trials will be sustained over time.

Effect of oxygen breathing and perfluorocarbon emulsion treatment on air bubbles in adipose tissue during decompression sickness

Decompression sickness (DCS) after air diving has been treated with success by means of combined normobaric oxygen breathing and intravascular perfluorocarbon (PFC) emulsions causing increased survival rate and faster bubble clearance from the intravascular compartment. The beneficial PFC effect has been explained by the increased transport capacity of oxygen and inert gases in blood. However, previous reports have shown that extravascular bubbles in lipid tissue of rats suffering from DCS will initially grow during oxygen breathing at normobaric conditions. We hypothesize that the combined effect of normobaric oxygen breathing and intravascular PFC infusion could lead to either enhanced extravascular bubble growth on decompression due to the increased oxygen supply, or that PFC infusion could lead to faster bubble elimination due to the increased solubility and transport capacity in blood for nitrogen causing faster nitrogen tissue desaturation. In anesthetized rats decompressed from a 60-min hyperbaric exposure breathing air at 385 kPa, we visually followed the resolution of micro-air bubbles injected into abdominal adipose tissue while the rats breathed either air, oxygen, or oxygen breathing combined with PFC infusion. All bubble observations were done at 101.3 kPa pressure. During oxygen breathing with or without combined PFC infusion, bubbles disappeared faster compared with air breathing. Combined oxygen breathing and PFC infusion caused faster bubble disappearance compared with oxygen breathing. The combined effect of oxygen breathing and PFC infusion neither prevented nor increased transient bubble growth time, rate, or growth ratio compared with oxygen breathing alone. We conclude that oxygen breathing in combination with PFC infusion causes faster bubble disappearance and does not exacerbate transient bubble growth. PFC infusion may be a valuable adjunct therapy during the first-aid treatment of DCS at normobaric conditions.

An atropine and glycopyrrolate combination reduces mortality in organophosphate poisoning

Anticholinergics are the mainstay of the pharmacological management of organophosphate poisoning (OPP). Atropine has the potential to cause central toxicity which may complicate the management of this life-threatening condition. A combination of atropine and glycopyrrolate in equivalent dosages titrated to the peripheral muscarinic signs, theoretically reduces the central effect of the anticholinergics by 50% and thereby the risk of central toxicity, while it provides effective control of the peripheral manifestations of OPP. This study reports the clinical morbidity and mortality associated with the management of OP with this anticholinergic combination over a 4-year period, 2003 to 2006, at Tygerberg Academic Hospital (TAH). Two of the 53 patients treated for OPP died, with this mortality lower than that previously reported at TAH. Atropine toxicity was evident in 12 (22.5%) patients and responded to a temporary cessation of the combination infusion. The demographic profile, presenting symptoms, duration of stay and complications encountered were similar to previous reports from TAH. Patients treated with the infusion of a combination of atropine and glycopyrrolate had a lower mortality rate compared with earlier reports from the same unit, but the occurrence of atropine toxicity was unchanged despite the hypothesized theoretical advantage.

Forearm and leg amino acid metabolism in the basal state and during combined insulin and amino acid stimulation after a 3‐day fast

Fasting is characterized by a progressive loss of protein, but data on protein kinetics are unclear and few have studied the effects of re-feeding. The present study was designed to test the hypothesis that a combined infusion of insulin and amino acids after fasting would induce compensatory increases in protein synthesis and reductions in protein breakdown at the whole body level and in muscle. We included 10 healthy male volunteers and studied them twice: (1) in the post-absorptive state and (2) after 72 h of fasting. Amino acid kinetics was measured using labelled phenylalanine and tyrosine, whole body energy expenditure was assessed and urea nitrogen synthesis rates were calculated. After fasting we observed an increase in arterial blood concentration of branched chain amino acids and a decrease in gluconeogenic amino acids (P < 0.05). Isotopically determined whole body, forearm and leg phenylalanine fluxes were unaltered apart from a 30% decrease in phenylalanine-to-tyrosine conversion (2.0 vs. 1.4 mumol kg(-1) h(-1), P < 0.01). During infusion of insulin and amino acids, amino acid concentrations increased. Our data indicate that after a 72-h fast basal and insulin/amino acid-stimulated regional phenylalanine fluxes in leg and forearm muscle are unaltered. During fasting concentrations of gluconeogenic amino acids decrease and hepatic and/or renal phenylalanine-to-tyrosine conversion decreases. Thus, as opposed to glucose and lipid metabolism, fasting does not induce insulin resistance as regards amino acid metabolism.

Heated (37°C) oxaliplatin infusion in combination with capecitabine for metastatic colorectal carcinoma: can it reduce neuropathy?

Oxaliplatin-associated neuropathy remains a dose-limiting toxicity of the standard chemotherapy regimen of oxaliplatin and capecitabine for metastatic colorectal cancer. No preventive strategy has definitively been established. Because this neuropathy is triggered by cold, we hypothesized that infusing oxaliplatin at 37 degrees C might reduce neuropathy. In this open-label pilot feasibility trial, patients with no prior chemotherapy for metastatic colorectal cancer were included. Treatment consisted of capecitabine 1,000 mg/m(2) bid on days 1-14 and oxaliplatin 130 mg/m2 on day 1 of a 21-day cycle. The oxaliplatin infusion was administered through a fluid-warming device at a constant temperature of 37 degrees C over 2 h. The primary endpoint was feasibility and drug reactions during the infusion. Secondary endpoints included acute and chronic neuropathy as well as response rate. Twenty patients were enrolled, and a total of 95 cycles administered. Median cumulative oxaliplatin dose was 735 mg/m(2). Apart from one patient with laryngeal spasm, no other infusion-related adverse events were observed. Of the patients, 35% reported grade 3/4 acute dysesthesia or paresthesia according to a patients questionnaire. Chronic neuropathy according to NCI CTC v3.0 was observed in 85% (grade 1) and 15% (grade 2), respectively. The overall response rate was 45% (95% CI 23-67%; 5% complete remission; 40% partial remission) and stable disease was achieved in another 30% of patients. Administration of heated oxaliplatin in combination with capecitabine is feasible and well tolerated without additional toxicity. While we have observed a relatively low rate of chronic cumulative neuropathy with heated oxaliplatin, this procedure appears not promising enough for us to recommend its further clinical evaluation.

Gemcitabine in Brief versus Prolonged Low-Dose Infusion, both Combined with Cisplatin, for Advanced Non-small Cell Lung Cancer: A Randomized Phase II Clinical Trial

Gemcitabine in low dose in prolonged infusion is a treatment with documented activity against a variety of tumors. We here report the first randomized trial to compare standard brief and low-dose prolonged infusion of gemcitabine. Eligible patients had non-small cell lung cancer in stage IIIB (wet) or IV, Karnofsky performance status 100 to 70 (Eastern Cooperative Oncology Group 0-2), measurable disease, were chemonaïve and fulfilled the standard criteria for chemotherapy. In arm A (standard treatment), gemcitabine was given at 1250 mg/m(2) in 20 to 30 minutes and in arm B (prolonged infusion) at 250 mg/m(2) in 6 hours infusion. All patients received gemcitabine on days 1 and 8 and cisplatin at 75 mg/m(2) on day 2 of a 3-week cycle for four cycles, followed by two cycles of gemcitabine as monotherapy. A total of 249 patients (188 men and 61 women, median age 58 years) were randomized between arm A (125 patients) and arm B (124 patients). Adenocarcinoma (53.9%) was the predominant histologic type; 92% of patients were in stage IV. The two groups were balanced for prognostic factors; however, group A had fewer patients with significant weight loss and no patient with lung cancer as a second malignancy or after radiotherapy for brain metastases. Grade 3 or greater toxicity was rare: anemia in 0.8 and 3.2%, neutropenia in 21.6 and 22.6%, thrombocytopenia in 0 and 1.6%, and nausea/vomiting in 4 and 8.1% for arms A and B, respectively. Alopecia was seen in 54.5% of patients in arm B, as compared with 9.7% in arm A. No patient died of treatment-related toxicity. During cycle 5, 47.7% of patients in arm A and 60.7% in arm B reported improved well-being, as compared with the status before chemotherapy. Patients in arm A had no complete remission, 32.8% partial responses, 48% minimal responses or stable disease, 13.6% progressions, and 5.6% were not evaluable. For arm B, the corresponding figures are as follows: complete remission 0.8%, partial responses 46% (for overall response rate of 46.8%), minimal responses or stable disease 36.3%, progression 12.1%, and not evaluable 4.8%. Median progression-free survival was 5.5 and 6.0 months, median overall survival was 10.1 and 10.0 months, and 1-year survival was 46.6 and 41.1% for arms A and B, respectively. For the 71 patients with squamous carcinoma, arm B seems superior to arm A, as seen by the higher overall response rate (51.3 versus 35.5%), longer median progression-free survival (6.2 versus 4.9 months), and longer median survival (11.3 versus 8.5 months). However, because of the small number of patients, these differences did not reach the level of statistical significance. In the treatment of advanced non-small cell lung cancer, gemcitabine in low dose in prolonged infusion in combination with cisplatin has low toxicity and has activity comparable with gemcitabine in higher dose in standard brief infusion. Low-dose gemcitabine may be preferred for incurable cancer among economically deprivileged patients. In addition, apparent superior activity against squamous carcinoma opens new perspectives and deserves further research.

The influence of donor specific vertebral body derived bone marrow cell infusion on canine islet allograft survival without irradiation conditioning of the recipient.

In recent studies in rodents, it was shown, that donor specific tolerance towards islet allografts without irradiation therapy of the recipient is induced by bone marrow cell infusion in combination with temporary immunosuppression. In the present study, the effect of donor specific bone marrow cell (DBMC) infusion at the time of intrahepatic islet allotransplantation without irradiation conditioning of the recipient was investigated in the canine model, paralleling ongoing clinical trials. It was observed, that unfractionated bone marrow cells given simultaneous to islet allografts led to higher frequencies of rejection periods and decreased islet allograft survival, when administered to recipients immunosuppressed with Cyclosporine A only. In contrast, an additional short inductive treatment of the recipient with an anti-dog-T-lymphocyte monoclonal antibody (5G2) abrogated the enhanced immunogenicity of the unfractionated bone marrow preparation, prolonging islet allograft survival with no rejection episodes observed during the immunosuppressive treatment with Cyclosporine. The composition of bone marrow cells might have contributed to the higher immunogenicity, since the percentage of MHC-class II antigen bearing cells is similar to man, but significantly higher than compared to rodents. It is therefore suggested, that further studies should encompass both timing of bone marrow cell infusion, appropriate immunosuppression and strategies to functionally inactivate mature MHC-class-II positive cells prior to DBMC infusion.

Effects of dobutamine on cardiac index and arterial blood pressure in isoflurane‐anaesthetized horses under clinical conditions

Volatile agent-induced hypotension may contribute to anaesthetic-related morbidity and mortality in horses. Dobutamine is commonly used to support arterial blood pressure (ABP) but little is known about its cardiovascular effects under clinical conditions. The aim of this clinical study was to elucidate the relationship between cardiovascular function and dobutamine infusion in isoflurane-anaesthetized horses. Forty-four horses anaesthetized for a variety of surgical procedures were studied. Premedication with acepromazine, methadone and detomidine was followed by induction of anaesthesia with ketamine and midazolam. Anaesthesia was maintained with isoflurane vaporized in oxygen. Routine anaesthetic monitoring was applied and cardiac output was measured by lithium dilution. Dobutamine was infused to maintain mean ABP above 70 mmHg. The relationship between dobutamine infusion rate, heart rate (HR), ABP and cardiac index was investigated immediately prior to (T(0)) and 15 min (T(1)) after dobutamine infusion started, followed at 30 min intervals (T(2), etc.). Arterial blood pressure increased significantly after dobutamine infusion started, HR and cardiac index increased significantly only with dobutamine infusion in combination with surgical stimulus. Although isoflurane decreases blood pressure mainly by vasodilation, dobutamine is an effective treatment for hypotension under clinical conditions in isoflurane-anaesthetized horses. The effect of dobutamine is not directly proportional to dose and surgical stimulus probably contributes to the cardiovascular improvement.

Pharmacokinetics of intraperitoneal docetaxel and S-1 in patients with gastric cancer with peritoneal carcinomatosis

e15626 Background: One of the most causes of death from gastric cancer is peritoneal cartinomatosis. Intraperitoneal docetaxel infusion is expected to be a new strategy for a treatment of peritoneal carcinomatosis. The purpose of this study is to evaluate the plasma and peritoneal pharmacokinetic of intraperitoneal docetaxel infusion in combination with oral administration of S-1. Methods: Eight patients with peritoneal carcinomatosis of advanced gastric cancer were enrolled. Docetaxel was dissolved in an isotonic saline to a final 1 liter solution and administered in 2 hour via an implanted intraperitoneal catheter at dosage of 40mg/m2. Five of eight patients were administered S-1 orally at dosage of 80mg/m2. Blood and peritoneal fluid were collected before administration, on completion of the docetaxel infusion(hour 0) and at hours 1,2,4,6,12,24,48,and 72 after completion of the infusion of the docetaxel. Plasma and peritoneal fluid concentrations of docetaxel and 5FU were evaluated. Results: The mean peak peritoneal and plasma concentrations of docetaxel were 18.6×103 ng/ml (at hour 0) and 45 ng/ml (at hour 0 to 2), respectively. The peritoneal concentrations of docetaxel were remained even after 24 and 72 hours (24 hours: 1150ng/ml, 72 hours: 74ng/ml). In seven out of eight patients, plasma concentrations of docetaxel were disappeared after 24 hours, but in only one patient with severe ascites, concentration of plasma docetaxel at hour 24 could be obtained (20 ng/ml). The mean peritoneal and plasma areas under the curves (AUC) of docetaxel were 141×103 ng/ml×hr and 480 ng/ml×hr, respectively. The mean peritoneal concentrations of 5FU kept over 60% of plasma concentrations (plasma: 164.3ng/ml, peritoneal: 105ng/ml). Conclusions: Intaperitoneal docetaxel kept relatively high concentrations even after 72hours. 5FU concentrations were well transfered in peritoneal fluid from plasma via oral S-1 administration. Intraperitoneal docetaxel in combination with S-1 orally may be a useful regimen to the patients with carcinomatosis of advanced gastric cancer. No significant financial relationships to disclose.

A phase II study of a 1-hour infusion of romidepsin combined with bortezomib for multiple myeloma (MM) patients with relapsed or refractory disease

e19508 Background: Nonclinical studies have demonstrated that histone deacetylase inhibitors (HDACi) significantly reduce the growth of MM cells and enhance cytotoxicity of the proteasome inhibitor bortezomib (Velcade). Romidepsin, a pan-HDACi, has previously shown activity for patients (pts) with relapsed or refractory MM when administered as a 4-hr infusion in combination with dexamethasone and bortezomib. Methods: This open-label, multi-center, phase II study (GPI-08–0006) was initiated to evaluate the activity and safety of a 1-hr infusion of romidepsin in combination with bortezomib for MM pts with relapsed or refractory disease and to evaluate the safety and single dose pharmacokinetics (PK)/pharmacodynamics of romidepsin in the first 5 pts. Pts received 10 mg/m2 romidepsin on days 1, 8 and 15 and 1.0 mg/m2 bortezomib on days 1, 4, 8 and 11 of a 28-day cycle. PK sampling and triplicate ECGs were performed at 0, 0.25, 0.5, 1, 2, 3, 4, 6 and 24 hrs after initiation of the first 1-hr infusion of romidepsin. Results: To date, 5 pts have been enrolled (median age 68 [range, 65–72]) 2 pts who relapsed from recent bortezomib-containing regimens experienced minimal responses after 2 cycles. 2 pts have experienced grade 3 thrombocytopenia. No pt had a QTcF value of &gt;480 ms the mean change in QTcF from baseline to Cmax was 4.2 ms (-10 to 13). Values for PK parameters are included in the table . When compared with data from pts who were treated with a 4-hr infusion of 14 mg/m2, the Cmax of the 1-hr infusion of romidepsin 10 mg/m2 was ∼ 20% higher and exposure (AUC0–24hr) was reduced by 70%. Conclusions: Preliminary data suggest that the 1-hr infusion of romidepsin combined with bortezomib is active for pts with MM relapsed or refractory to bortezomib. Based on the initial incidence of grade 3 thrombocytopenia and PK data, additional pts are being treated on the same schedule but with a reduced dose of romidepsin (8 mg/m2). This study continues to enroll pts. [Table: see text] [Table: see text]

Pharmacokinetics of intraperitoneal docetaxel and S-1 in patients with gastric cancer with peritoneal carcinomatosis

e15672 Background: One of the most causes of death from gastric cancer is peritoneal cartinomatosis. Intraperitoneal docetaxel infusion is expected to be a new strategy for a treatment of peritoneal carcinomatosis. The purpose of this study is to evaluate the plasma and peritoneal pharmacokinetic of intraperitoneal docetaxel infusion in combination with oral administration of S-1. Methods: Eight patients with peritoneal carcinomatosis of advanced gastric cancer were enrolled. Docetaxel was dissolved in an isotonic saline to a final 1 liter solution and administered in 2 hour via an implanted intraperitoneal catheter at dosage of 40mg/m2. Five of eight patients were administered S-1 orally at dosage of 80mg/m2. Blood and peritoneal fluid were collected before administration, on completion of the docetaxel infusion(hour 0) and at hours 1,2,4,6,12,24,48,and 72 after completion of the infusion of the docetaxel. Plasma and peritoneal fluid concentrations of docetaxel and 5FU were evaluated. Results: The mean peak peritoneal and plasma concentrations of docetaxel were 18.6×103 ng/ml (at hour 0) and 45 ng/ml (at hour 0 to 2), respectively. The peritoneal concentrations of docetaxel were remained even after 24 and 72 hours (24 hours: 1150ng/ml, 72 hours: 74ng/ml). In seven out of eight patients, plasma concentrations of docetaxel were disappeared after 24 hours, but in only one patient with severe ascites, concentration of plasma docetaxel at hour 24 could be obtained (20 ng/ml). The mean peritoneal and plasma areas under the curves (AUC) of doceta×el were 141x103 ng/ml×hr and 480 ng/ml×hr, respectively. The mean peritoneal concentrations of 5FU kept over 60% of plasma concentrations (plasma: 164.3ng/ml, peritoneal: 105ng/ml). Conclusions: Intaperitoneal docetaxel kept relatively high concentrations even after 72hours. 5FU concentrations were well transfered in peritoneal fluid from plasma via oral S-1 administration. Intraperitoneal docetaxel in combination with S-1 orally may be a useful regimen to the patients with carcinomatosis of advanced gastric cancer. No significant financial relationships to disclose.

Randomized, phase II study comparing interferon combined 5-fluorouracil plus cisplatin hepatic arterial infusion with interferon combined 5-fluorouracil hepatic arterial infusion in patients with advanced hepatocellular carcinoma

4588 Background: This randomized phase II trial compared the response rate (RR) of interferon (IFN) combined 5-fluorouracil (5FU) plus cisplatin (CDDP) hepatic arterial infusion (HAI) with IFN combined 5FU HAI in advanced hepatocellular carcinoma. Methods: Patients (pts) with measurable histologically or radiologically confirmed advanced hepatocellular carcinoma (major vascular invasion and/or bilobular multiple ≥5 nodules) were randomized into 2 groups. Arm A (n=57): continuous 5FU HAI (300mg/m2 day1–5, day8–12), CDDP HAI (20mg/m2, day 1, day 8 for 1.5 hours). IFN alpha-2b (3M IU/body) was administrated intramuscularly 3 times per week for 4 weeks. The treatment cycles repeated for 6 weeks. Arm B (n=57): IFN combined 5FU HAI with same dose without CDDP infusion. Treatment was continued until disease progression. The primary endpoint was RR. The secondary endpoints were overall survival (OS), time to progression (TTP) and toxicity. Results: Results for responses are presented for 109 pts and toxicity for 114 pts. The best overall response rate (RR) was 46% for group A and 25% for group B. This included 1 (2% of group A) vs. 3 (6% of group B) complete responses, and 25 (44% of group A) vs. 11 (19% of group B) partial responses. Fifteen pts in group A (26%) vs. 19 pts (33%) in group B had stable disease and 13 pts (23%) vs. 22 (39%) in respectively group A and B progressed while on treatment. RR was significantly higher in group A (p=0.02). The median TTP was 6.5 ± 2.0 months (mo) for group A vs. 3.3 ± 2.0 mo for group B (p=0.005). The median OS was 17.6 ± 3.2 mo for group A vs. 10.5 ±2.3 mo for group B (p=0.38). The median OS was 13.7 ± 4.9 mo for both groups. Grade 3/4 toxicity occurred in 65.8% of pts. Hematological toxicity was common and occurred in 53.5%. The thrombocytopenia and infusion port-related toxicity occurred more frequently in group A. Conclusions: IFN combined 5FU plus CDDP HAI shows higher antitumor activity and longer TTP than IFN combined 5FU HAI. Although OS is also longer without significant difference, these results show the clinical efficacy of additional CDDP to IFN combined 5FU HAI. No significant financial relationships to disclose.

Cap-dependent translation blockade and fixed dose-rate gemcitabine: Interaction in an in vitro bioreactor system

Translation initiation commences with the binding of eIF-4F to the mRNA 5′-end cap. eIF-4F binds the cap structure via its eIF-4E subunit, which is the rate-limiting step for the initiation of translation. This pathway can be inhibited by 4E-binding proteins (4E-BPs). The present study investigated prolonged gemcitabine infusion in combination with reduced eIF-4E function on NSCLC cell viability in an in vitro bioreactor system. To assess attachment to the hollow fibers, cells with dominant active 4E-BP1 were first analyzed by scanning electron microscopy. Cells were treated with 0.5- or 2.5 h (fixed dose rate) infusion (same total dose), simulating human plasma gemcitabine concentration–time profiles. An interaction was observed between fixed dose rate infusion gemcitabine and presence of dominant active 4E-BP1. We conclude that cap-dependent translation blockade and fixed dose rate infusion gemcitabine treatment results in a significant interaction affecting cell viability in vitro.

Safety and Pharmacokinetics of Chimeric Anti-Shiga Toxin 1 and Anti-Shiga Toxin 2 Monoclonal Antibodies in Healthy Volunteers

Shiga toxin (Stx)-producing Escherichia coli (STEC) causes hemorrhagic colitis and hemolytic-uremic syndrome (HUS). The rates of STEC infection and complications, including death, are highest among young children and elderly individuals. There are no causal therapies. Because Stx is the primary pathological agent leading to organ injury in patients with STEC disease, therapeutic antibodies are being developed to neutralize systemically absorbed toxin during the early phase of the infection. Two phase I, single-dose, open-label, nonrandomized studies were conducted to evaluate the safety and pharmacokinetics of the chimeric monoclonal antibodies (antitoxins) against Stx 1 and 2 (calphaStx1 and calphaStx2, respectively). In the first study, 16 volunteers received 1 or 3 mg/kg of body weight of calphaStx1 or calphaStx2 as a single, short (1-h) intravenous infusion (n = 4 per group). In a second study, 10 volunteers received a 1-h infusion of calphaStx1 and calphaStx2 combined at 1 or 3 mg/kg (n = 5 per group). Treatment-emergent adverse events were mild, resolved spontaneously, and were generally unrelated to the antibody infusion. No serious adverse events were observed. Human antichimeric antibodies were detected in a single blood sample collected on day 57. Antibody clearance was slightly greater for calphaStx1 (0.38 +/- 0.16 ml/h/kg [mean +/- standard deviation]) than for calphaStx2 (0.20 +/- 0.07 ml/h/kg) (P = 0.0013, t test). The low clearance is consistent with the long elimination half-lives of calphaStx1 (190.4 +/- 140.2 h) and calphaStx2 (260.6 +/- 112.4 h; P = 0.151). The small volume of distribution (0.08 +/- 0.05 liter/kg, combined data) indicates that the antibodies are retained within the circulation. The conclusion is that calphaStx1 and calphaStx2, given as individual or combined short intravenous infusions, are well tolerated. These results form the basis for future safety and efficacy trials with patients with STEC infections to ameliorate or prevent HUS and other complications.

P-61 Heart Failure Causes Platelet Activation, through Impaired Endothelial Function

Heart Association stage D HF received intermittent outpatient infusions once or twice a week. Carperitide, olprinone, and catecholamines (dopamine or dobutamine) were administered to 8 patients (57 infusions of mean 0.033mg/kg/min for mean 3.7 hour), 20 patients (79 infusions of mean 0.11mg/kg/min for mean 3.8 hour), and 5 patients (115 infusions of mean 3.2mg/kg/min for mean 3.3 hour), respectively. Intravenous furosemide was also administered. Mean follow-up periods were 32.2±32.1 months (range: 2 95 months), and 14 deaths (9 deaths due to HF, 4 sudden deaths, 1 death from cancer) occurred. All-cause mortality at 20 months (median followup periods) was 34.9% by Kaplan-Meier method. Compared with pre-infusion periods, there were 62.7% reduction in the length of HF hospitalizations (p < 0.05), 22.2% reduction in the number of HF hospitalizations (p = 0.33), and 51.0% reduction in cost (p = 0.086), at post-infusion periods. Conclusions: In patients with advanced HF, intermittent outpatient infusions of combination of inotropes and carperitide may have some clinical benefits without worsening mortality.

Ice-Cold Saline for the Induction of Mild Hypothermia in Patients With Acute Ischemic Stroke

Neuroprotective effects of induced hypothermia depend on its time point of initiation after acute brain injury. Preliminary studies in cardiac arrest patients indicate that rapid infusion of ice cold saline (ICS) is safe and effective for induction of hypothermia. We investigated its use in patients with acute ischemic stroke (AIS). Patients (n=10) with AIS were included within 3 hours after symptom onset. After cranial CT, they were treated-if indicated-with rt-PA. ICS of 4 degrees C (25 mL/kg body weight) was administered via peripheral intravenous lines. Patients received buspirone/pethidine to prevent and treat shivering. After infusion of the target volume of ICS, no further efforts were made to maintain hypothermia by other methods. Ten patients with a median National Institutes of Health Stroke Scale (NIHSS) score of 5.5 (range 4 to 12) on admission were included into the study. Nine patients were treated with thrombolysis within a time window of 104+/-25 minutes. A mean amount of 2163+/-256 mL ICS was infused 17+/-11 minutes after rt-PA infusion had started. Tympanic temperature dropped significantly by a maximum of 1.6+/-0.3 degrees C (P<0.005) at 52+/-16 minutes after ICS was started. The procedure was well tolerated. The NIHSS score improved significantly to a median of 1 (range 1 to 15) at discharge compared to admission (P<0.02). This pilot study suggests that rapid ICS infusions in combination with pethidine and buspirone lower the body temperature significantly without major side effects.

Leptin Augments the Acute Suppressive Effects of Insulin on Hepatic Very Low-Density Lipoprotein Production in Rats

It is well established that leptin increases the sensitivity of carbohydrate metabolism to the effects of insulin. Leptin and insulin also have potent effects on lipid metabolism. However, the effects of leptin on the regulation of liver lipid metabolism by insulin have not been investigated. The current study addressed the effects of leptin on insulin-regulated hepatic very low-density lipoprotein (VLDL) metabolism in vivo in rats. A 90-min hyperinsulinemic/euglycemic clamp (4 mU/kg x min(-1)) reduced plasma VLDL triglyceride (TG) by about 50% (P < 0.001 vs. saline control). Importantly, a leptin infusion (0.2 microg/kg x min(-1)) in combination with insulin reduced plasma VLDL-TG by about 80% (P < 0.001 vs. insulin alone). These effects did not require altered skeletal muscle lipoprotein lipase activity but did include differential effects of insulin and leptin on liver apolipoprotein (apo) B and TG metabolism. Thus, insulin decreased liver and plasma apoB100/B48 levels (approximately 50%, P < 0.01), increased liver TGs (approximately 20%, P < 0.05), and had no effect on fatty acid oxidation. Conversely, leptin decreased liver TGs (approximately 50%, P < 0.01) and increased fatty acid oxidation (approximately 50%, P < 0.01) but had no effects on liver or plasma apoB levels. Importantly, the TG-depleting and prooxidative effects of leptin were maintained in the presence of insulin. We conclude that leptin additively increases the suppressive effects of insulin on hepatic and systemic VLDL metabolism by stimulating depletion of liver TGs and increasing oxidative metabolism. The net effect of the combined actions of insulin and leptin is to decrease the production and TG content of VLDL particles.

Angiotensin II Secretion by the Bovine Oviduct is Stimulated by Luteinizing Hormone and Ovarian Steroids

Angiotensin II (Ang II), a vasoactive peptide, is secreted by the bovine oviduct and is involved in modulation of local oviductal contraction. Ang II biosynthesis and release during the normal estrous cycle and the effects of luteinizing hormone (LH) and ovarian steroids on biosynthesis and secretion of Ang II were investigated. During the preovulatory period, increases in mRNA expression for Angiotensin converting enzyme 1 (ACE-1) and release of Ang II peptide were detected. Microdialysis of oviductal segments in vitro showed that LH alone significantly increased Ang II release, and combined infusion of LH+E(2)+P(4) caused an increase in Ang II release. In cultured oviductal epithelial cells, LH increased Ang II release and ACE-1 mRNA expression, and E(2)+P(4) enhanced stimulatory effect of LH on Ang II release and ACE-1 mRNA expression. Thus, it can be concluded that the oviductal Ang II system is upregulated by LH and ovarian steroids during the periovulatory period and may enhance local oviductal contraction. These events could stimulate transport of gametes to the fertilization site.